Over the past three decades a growing number of cancer-driving protein kinases have been successfully targeted as reflected in the approval of 49 kinase inhibitors by the Food and Drug Administration (FDA). Recent approval of the first tyrosine kinase inhibitor (Larotrectinib) for treatment of any cancer bearing mutation in neurotrophic receptor kinase validated a novel paradigm of precision targeting of the molecular driver rather than treatment based on cancer type defined by anatomic sites. The receptor tyrosin kinase (RTK) known as rearranged during transfection (RET) is mutated or chromosomally rearranged in multiple malignancies including 2% of non-small cell lung cancers (NSCLC), 20?80% of sporadic medullary thyroid cancers (MTC) and >95% of patients with familial MTC and multiple endocrine neoplasia 2 (MEN2) leading to very poor prognosis for these patients. Currently two RET inhibitors, cabozantinib and vandetanib, have been FDA approved for treatment of MTC and none is approved for treatment of RET-driven NSCLC. These agents have poor activity towards clinically important RET mutants including the gatekeeper mutations V804L/M. Two new, more potent RET- specific drugs Loxo-292 and Blu-667 are in clinical development. Our recent findings have identified additional RET mutants that are resistant to Loxo-292 and Blu-667. Given the evolution of mutational landscape upon introduction of new inhibitors, a pipeline of novel and potent inhibitors is critical for meeting this challenge. We have developed a novel chemical scaffold with potent activity against a wide range of clinically relevant RET mutants. These compounds exhibit orders of magnitude superior activity compared to cabozantinib and vandetanib, and potent activity towards mutants that are resistant to LOXO-292 and Blu667. The compounds are orally bioavailable. The objective of this multiple PI (MPI) Phase I STTR is to complete the lead optimization and selection of the final candidate for advanced development. In Aim 1, a set of up to 15 analogs will be characterized for RET-specific inhibitory activity against a range of mutants and RET fusions. Preliminary safety and bioavailability profile will be evaluated to exclude compounds with potential liabilities. Up to 4 lead compounds will be then tested in Aim 2 for in vivo activity in xenograft models of RET-driven thyroid cancer, a novel transgenic model of NSCLC driven by a RET fusion, as well as an allograft model of LOXO-292 and Blu- 667 resistant RET mutant. The expected final outcome of this Phase I STTR will be a lead and a back-up candidate for further advanced development under a follow-on Phase II project.